Abstract 5864: An angiogenic target of immune exclusion with checkpoint blockade in melanoma
Authors: Saba Tabasum, Dinesh Thapa, Anita Giobbie-Hurder, Jason L. Weirather, Xinqi Wu, Marco Campisi, Xiaoyun Li, Jingjing Li, Michael P. Manos, David A. Barbie, F. Stephen Hodi
Journal: Cancer Research (2023)

Abstract With the development of immune checkpoint blockade to treat a variety of malignancies, better predictive biomarkers as well as new targets to further improve anti-tumor immunity remains a need. Our understanding of the role of angiogenesis in immune regulation continues to improve, and combinations of anti-angiogenesis and immune checkpoint blockade demonstrate improved clinical efficacy, as well as mechanisms for improved immune cell trafficking. Tumor biopsies from a phase I study with 46 advanced melanoma patients treated with Ipilimumab and Bevacizumab combination (Ipi-Bev) therapy, revealed activated endothelium accompanied by lymphocyte infiltration. To discover possible targets involved in the observed clinical benefit, a serological screen was performed using human protein arrays with post-treatment plasma samples of long-term patients with clinical benefit to Ipi-Bev therapy (Wu et. al., 2017; Hodi et. al., 2014). EDIL3 (EGF Like Repeats and Discoidin Domains 3), a pro-angiogenic extracellular matrix protein, was identified. Humoral responses against EDIL3 were associated with favorable clinical outcomes including improved response rates (p=0.003) and overall survival (p=0.03) to Ipi-Bev therapy. The anti-EDIL3 response was also observed to be significantly (p=0.03) related to Ipi-Bev treatment when compared with patients treated with Ipilimumab alone, anti-PD1 therapy alone, or the combination of Ipilimumab and Nivolumab in a combined analysis. Transcriptome analyses of TCGA SKCM (n=469) and BMS Checkmate 064 trial (n=90) related upregulated EDIL3 expression with enrichment of EMT, TGFβ signaling in fibroblasts, and angiogenesis signatures. Interestingly, TIDE analysis demonstrated a role for EDIL3 in T cell exclusion and immunosuppressive cancer-associated fibroblasts (CAFs) as its source in the tumor microenvironment. EDIL3 was also predicted as a biomarker of non-response to immune checkpoint blockade treatment. In vitro studies confirmed the upregulation of EDIL3 expression and secretion by patient-derived CAFs along with its role in modulating TGFβ1 mediated EMT. Mechanistically, EDIL3 was found to interfere with leukocyte-endothelial interactions by disturbing LFA-1/ICAM1 mediated adhesion and inhibited T cell transmigration in 2-D and microfluidic 3-D coculture studies with patient-derived tumor endothelial cells. Our findings suggest that the humoral response against EDIL3 may serve as one of the underlying mechanisms involved in effectuating an excluded to an inflamed phenotype observed in responders of checkpoint blockade treatment. This study develops EDIL3 as a potential target to enhance cytotoxic immune responses and improve the outcomes of combination immune therapy. Studies are ongoing for targeted inhibition of EDIL3 with implications for therapeutic application to promote anti-tumor immunity. Citation Format: Saba Tabasum, Dinesh Thapa, Anita Giobbie-Hurder, Jason L. Weirather, Xinqi Wu, Marco Campisi, Xiaoyun Li, Jingjing Li, Michael P. Manos, David A. Barbie, F. Stephen Hodi. An angiogenic target of immune exclusion with checkpoint blockade in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5864.